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Abstract: TH-OR009

Human Recombinant Alkaline Phosphatase (recAP) Protection from Kidney Ischemia-Reperfusion Injury (IRI) Is Mediated by Dephosphorylation of ATP to Adenosine and Activation of Adenosine A2a Receptors

Session Information

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms


  • Rosin, Diane L., University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Hall, James Perry, Pfizer Inc., Cambridge, Massachusetts, United States
  • Bree, Andrea G., Pfizer Inc., Cambridge, Massachusetts, United States
  • Zheng, Shuqiu, University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • Encarnacion, Iain M., University of Virginia School of Medicine, Charlottesville, Virginia, United States
  • van Elsas, Andrea, AM-Pharma B.V., Bunnik, Netherlands
  • Molitoris, Bruce A., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Okusa, Mark D., University of Virginia School of Medicine, Charlottesville, Virginia, United States

Acute kidney injury (AKI) results in high mortality (up to 50%), and surviving patients are at risk for progressive chronic kidney disease (CKD). ATP released from dying cells acts as a potent pro-inflammatory ‘danger’ signal. Alkaline phosphatase (AP), a common endogenous enzyme that de-phosphorylates ATP, appears to play a significant anti-inflammatory role in host defense and innate immunity. Human recombinant AP (recAP) is currently in Phase 2 clinical trials for treatment of sepsis-associated AKI. We hypothesized that recAP protects kidneys from IRI by metabolizing released extracellular ATP to adenosine, producing anti-inflammatory effects through activation of adenosine A2a receptors (A2aR).


RecAP (500-2000 U/kg, iv) ± ZM-241,385 (ZM, 20, 200 mg/kg, sc)(adenosine A2a receptor antagonist) were administered 1h before renal ischemia in mice and at times after ischemia in rats; kidney injury in mice was evaluated at 24h.


RecAP dose-dependently decreased kidney injury in WT mice after 26 min ischemia; the 80% decrease in plasma creatinine with 2000 U recAP/kg was prevented completely by co-administration with ZM (20 mg/kg). Enzymatically inactive (mutant) recAP was not protective, suggesting that ATP dephosphorylation is necessary for protection. RecAP also protected CD73-/- mice, which lack a 5’ ectonucleotidase that de-phosphorylates AMP to adenosine and are more sensitive to IRI than WT mice (22 min ischemia); this beneficial effect of recAP in CD73-/- mice (34% of control) was partially blocked by 200 mg/kg ZM (86% of control). In rats recAP ameliorated IRI when administered after initiation of acute injury, an effect reversed by ZM, thus providing relevance for therapeutic dosing of recAP clinically. In a CKD ischemic rat model, recAP given after the 3rd instance of IRI also significantly reduced renal injury (61% reduction).


These results strongly suggest that during renal IRI recAP promotes production of adenosine from liberated ATP in injured kidney tissue, thereby amplifying endogenous mechanisms that can reverse tissue injury, in part through A2aR-dependent anti-inflammatory signaling pathways.


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